Evaluation of Priming Before in Vitro Maturation for Fertility Preservation in Breast Cancer Patients: a Randomized Controlled Study

In vitro maturation (IVM) is an assisted reproductive technology which consists in the retrieval of immature cumulus-oocyte complexes (COCs) from small antral follicles, followed by their in vitro maturation in specific culture conditions. Oocytes having reached metaphase II (MII) stage after 24 to 48 hours of IVM can then be fertilized. This procedure was first developed for patients presenting polycystic ovarian syndrome (PCOS), in order to avoid ovarian hyperstimulation syndrome (OHSS), an iatrogenic consequence of exogenous gonadotropins administration. However, the increasing use of GnRH antagonist protocols allowing ovulation trigger with GnRH agonist has dramatically reduced the indication of IVM in women at risk of OHSS. Yet, evidence indicate that IVM may be considered for patients presenting FSH resistance or contraindications to controlled ovarian stimulation. The recent development of female fertility preservation (FP) renewed interest to this technique. Indeed, it can be performed without any prior ovarian stimulation and whatever the phase of the menstrual cycle. Although it is still considered experimental, oocyte vitrification following IVM has been applied in different groups of patients, in particular those diagnosed with breast cancer, autoimmune or ovarian diseases. In physiologic conditions, final follicular maturation is induced by a double FSH and LH release which occurs when the dominant follicle reaches approximately 17 to 20 mm in diameter. This gonadotropin surge usually precedes the follicular rupture and mature oocyte release from 36 to 40 hours. In case of an assisted reproductive treatment, two strategies can be used to reproduce this hormonal signal: (i) either an injection of hCG, which binds to the LH receptor on granulosa cells, (ii) or a GnRH agonist (GnRHa) administration which induces an endogenous double peak of LH and FSH through a "flare up effect". Miming common practice for in vitro fertilization, priming with hCG or GnRHa injection 36 hours before the COCs retrieval has been suggested for patients undergoing IVM procedure in order to improve oocyte maturation rates and further IVM outcomes. Indeed, it is hypothesized that these iatrogenic hormonal activities might enhance the final oocyte maturation in vivo, therefore shortening the duration of the overall IVM process. Actually, in PCOS patients, several line of evidence indicate that IVM outcomes are improved after hCG priming. This positive effect might be explained by a premature expression of LH receptors on granulosa cells of small antral follicles <10 mm in diameter. Nevertheless, in normo-ovulatory non PCOS patients, LH receptor expression in these follicles remains very low, questioning the relevance of providing LH activity to improve oocyte maturation during IVM cycles performed for FP. The present investigation aimed to test whether the absence of therapeutic intervention prior to oocyte retrieval modifies IVM outcomes when compared with cycles primed either with recombinant hCG or GnRH agonist in breast cancer patients.